Progesterone is essential for the normal morphologic development of the luteal phase endometrium, for implantation of a blastocyst and for maintenance of pregnancy. Surprisingly, given its critical role in reproduction, little is known about the mediator(s) of progesterone action. We are using a recently described progestin-dependent glycoprotein, placental protein 14 (PP14) and the antiprogestin RU 486 to probe progesterone action. We are investigating the relationship between endogenous progesterone production, serum PP14 concentrations and endometrial maturation in women with normal cycles. Up to 28% of normally cycling women had a delay in endometrial maturation of a biopsy obtained 7 - 9 days after the LH surge. Contrary to previous studies from other groups, the integrated and peak levels of PP 14 and progesterone did not correlate with the degree of endometrial maturation. Only two of 14 women having abnormal endometrial development had progesterone values below the range seen in women with normal endometrial development. These studies suggest that measurement of serum PP14 and progesterone concentrations may not be useful predictors of fecundity in normally cycling women. Further studies in infertile women and those with multiple miscarriages may give better insight into the cause of these disorders, however, since it is possible that the progesterone-mediated endometrial effects may be abnormal in these subgroups. We have found that IGF-1 and the proto-oncogene c-myc appear to mediate the effects of estrogen exposure and withdrawal on the processes of uterine proliferation and apoptotic regression in the mouse.